The invention relates to a process for preparing tocopheryl esters or tocotrienyl esters by acid-catalyzed esterification of a tocopherol or a tocotrienol in a solvent at elevated temperature with the appropriate carboxylic acid, in particular with sorbic acid.
A tocopherol means according to the invention a compound of the formula I 
where R1 to R3 are H or methyl, and the side chain is saturated, and a tocotrienol is a corresponding compound in which the dotted lines denote another bond.
The process is of particular interest for preparing carboxylic esters of xcex1-tocopherol, i.e. a compound where R1 to R3 are each methyl, and the side chain is saturated. xcex1-Tocopherol has the highest vitamin E activity.
xcex1-Tocopherol (vitamin E; VE) has recently attained great importance in livestock nutrition and as food supplement since it is the principal lipid-soluble biological antioxidant, and because of its additional biological effect. Since free tocopherols are very readily oxidized in air, they are preferably used in the form of their esters with carboxylic acids, which are relatively stable to atmospheric oxygen at room temperature. As is evident from formula I, tocopherols are compounds with a sterically hindered phenolic hydroxyl group and thus a hydroxyl group which is extremely difficult to esterify.
It is known about phenols themselves that although they react well with acid chlorides or anhydrides they do not react with carboxylic acids to give phenol esters (cf. Brockhaus Chemie, VEB F. A., Brockhaus Verlag Leipzig, 5th edition, 1987, Volume 2/L-Z, page 846-847, left-hand column, paragraph 3 or DBP 10 35 960). The same applies a fortiori to topopherols and tocotrienols with their sterically hindered OH group. Thus, the most important tocopheryl ester, tocopheryl acetate, is prepared industrially exclusively by reacting tocopherol with acetic anhydride.
A review of processes for preparing esters of xcex1-tocopherol with aliphatic or aromatic carboxylic acids is to be found in Izvestiya vysshikh uchebnykh zavedenii, Khimiya i khimicheskaya tekhnologiya, 1991, 34(11), 3-26, in particular 4-9. According to pages 4-5 of loc. cit., alkyl carbonates are prepared by reacting VE with phosgene and subsequently with alkanols in the presence of pyridine or by reacting VE with acid chlorides of the alkylcarboxylic acids. According to page 5 of loc. cit., the palmitate, stearate, propionate, caprate and p-nitrobenzoate are also prepared by reacting VE with the appropriate acid chlorides in the presence of pyridine at 50 to 62xc2x0 C. Although, according to page 5 of loc. cit., the palmitate and stearate can also be prepared by reacting VE with palmitic acid or stearic acid, this is only in the presence of costly exotic condensing agents such as carbonyldiimidazoles or thionyldiimidazoles. According to the foot of page 5 of loc. cit., succinates, malonates, glutarates and phthalates are prepared by reacting VE with a Grignard reagent and subsequently with anhydrides of the appropriate acids. According to page 6 of loc. cit., the malonate and phthalate are prepared by reacting VE with malonic anhydride and phthalic acid, respectively, in the presence of large amounts of ZnCl2 as dehydrating agent. According to page 8 of loc. cit., xcex1-tocopheryl methoxypolyoxyethyleneacetate is prepared by reacting VE with methoxypolyoxyethyleneacetic anhydride in the presence of p-toluenesulphonic acid (6 h) or in pyridine (6 days). According to page 8 of loc. cit., xcex1-tocopheryl p-chlorophenoxyisobutyrate, which has antiatherosclerotic activity, is prepared by reacting VE with p-chlorophenoxybutyric acid in the presence of costly carbonyldiimidazoles or with the appropriate acid chloride in the presence of pyridine or else by reacting VE with sodium methoxide in methanol and reacting the resulting sodium salt of VE with p-chlorophenoxyisobutyryl chloride. According to page 8 of loc. cit., xcex1-tocopheryl pivalate is prepared by condensing VE with pivalic acid in the presence of large amounts of pyrophosphate or under the influence of enzymes. According to the foot of page 8 of loc. cit., tocopheryl salicylate is prepared by condensing VE with salicylic acid in the presence of large amounts of tetraalkyl pyrophosphate. According to the top of page 9 of loc. cit., xcex1-tocopheryl cinnamate and xcex1-tocopheryl ferulate are prepared by reaction of the appropriate acid chlorides.
According to page 9 of loc. cit., the xcex1-tocopheryl esters of linoleic acid, oleic acid and arachidonic acid, which are in demand as compounds with antiatherosclerotic effect, are prepared by reacting VE with said acids and acid chlorides or anhydrides of said acids in the presence of large amounts of tetraalkyl pyrophosphate or other acid scavengers or else recently by reacting VE with the appropriate acids in the presence of costly carbonyldiimidazoles or thionyldiimidazoles.
Another xcex1-tocopheryl derivative of medical interest is xcex1-tocopheryl sorbate which is of interest as sunscreen agent. It is prepared as disclosed in EP 313 303 B1 by reacting 1 mol of VE with 4.3 mol of a polyphosphate ester and subsequently stirring with 1 mol of sorbic acid for 16 hours.
Another application described for tocopheryl sorbate is its use as ingredient of dermatological compositions for antiacne treatment (cf. U.S. Pat. No. 5,545,407).
As is evident from the cited prior art, xcex1-tocopheryl esters are mostly prepared in the prior art by reacting VE with carbonyl chlorides or carboxylic anhydrides. The disadvantages of this are that the acid chlorides or anhydrides must previously be prepared in an elaborate manner, that working with acid chlorides industrially is rather costly, and that it is necessary in many cases to operate in pyridine, which is not advantageous for vitamin derivatives because of its unpleasant properties (inter alia the odor).
In the cases where VE is esterified with the carboxylic acids themselves in the prior art, it is necessary also to use multiple molar amounts of dehydrating agents such as polyphosphate esters, tetraalkyl pyrophosphate or zinc chloride or else to have costly condensing agents such as carbonyldiimidazoles or thionyldiimidazoles present. The use of polyphosphate esters and tetraalkyl pyrophosphate is unsuitable on an industrial scale because of the costly preparation thereof. As is evident from EP 313 303, for example, there are technical problems in preparing polyphosphate esters owing to the use of the very hygroscopic P2O5, the hazardous diethyl ether and chloroform, and the long reaction time of 48 hours. Use of zinc chloride and the imidazoles containing chloride ions from their preparation makes severe demands on the reactor material and results in high costs.
It is an object of the present invention to develop a process for esterifying tocopherols and tocotrienols in which the tocopherols or tocotrienols can be esterified with the appropriate carboxylic acids in a simple and industrially worthwhile manner without the need also to use a large excess of dehydrating agent or else costly exotic condensing agents such as carbonyldiimidazole or thionyldiimidazoles.
We have found that this object is achieved by a process for preparing tocopheryl esters or tocotrienyl esters by acid-catalyzed esterification of a tocopherol or a tocotrienol in a solvent while stirring at elevated temperature, which comprises
a) carrying out the esterification with the appropriate carboxylic acid,
b) carrying out the esterification with from 2.5 to 6 mol. preferably 3 to 5 mol. of the carboxylic acid in an aliphatic, cycloaliphatic or aromatic hydrocarbon boiling in the range from 80 to 200xc2x0 C., preferably 110 to 130xc2x0 C., or else with from 1.0 to 2.5 mol, preferably 1 to 1.5 mol, of the carboxylic acid in a mixture consisting of an aliphatic or cycloaliphatic hydrocarbon boiling in the range from 80 to 200xc2x0 C. and a cyclic carbonate of the formula II or a xcex3-lactone of the formula III 
xe2x80x83where R1, R2 and R3 are each H or Cl-C4-alkyl, and R4 is H, C1-C4-alkyl, phenyl or methoxymethyl, as solvent,
c) using a nonoxidizing strong inorganic or organic acid, preferably sulfuric acid, boroxalic acid or benzene- or toluenesulfonic acids, in catalytic amounts as acid catalyst, and
d) continuously removing the water formed in the reaction by azeotropic distillation during the reaction.
Surprisingly, the cyclic carbonate and the xcex3-lactone remain stable under the reaction conditions and are not lost.
Examples of carboxylic acids which can be esterified with a tocopherol or tocotrienol by the process according to the invention are:
acetic acid, propionic acid, 1-n-hexanoic acid, caproic acid, sorbic acid, palmitic acid, stearic acid, oleic acid, linoleic acid and arachidonic acid.
The process according to the invention is of particular interest for reacting a tocopherol or a tocotrienol with acetic acid, propionic acid, sorbic acid, palmitic acid, stearic acid, oleic acid or linoleic acid as carboxylic acid.
It is possible to use as acid catalyst for the esterification reaction according to the invention a nonoxidizing strong inorganic or organic acid, ie. an acid with a pKa of about xe2x88x926 to 3. Examples of particularly suitable acids are sulfuric acid, boroxalic acid (ie. an approximately equimolar mixture of boric acid and oxalic acid), a toluenesulfonic acid or a benzenesulfonic acid. The acids are generally used in amounts of from 0.001 mol to 0.2 mol of catalyst acid per mole of tocopherol or tocotrienol. The process according to the invention is particularly advantageous on use of from 0.004 to 0.1 mol of sulfuric acid as acid catalyst per mole of tocopherol or tocotrienol for the esterification.
Aliphatic hydrocarbons boiling in the range from 80 to 200xc2x0 C., preferably 110 to 130xc2x0 C., which can be employed according to the invention and which may be mentioned are heptanes and octanes, in particular n-heptane or mixtures of hydrocarbons such as hexanes, heptanes, octanes and/or nonanes.
A cycloaliphatic hydrocarbon which may be mentioned as suitable for the process according to the invention is cyclohexane.
Aromatic hydrocarbons which may be mentioned as suitable for use in a one-phase system are benzene and toluene. If only hydrocarbons, ie. a one-phase system, are used as solvents, it is necessary in most cases to use a large molar excess of the carboxylic acid. The carboxylic acid is then advantageously used in amounts of about 3 to 5 mol of carboxylic acid per mole of tocopherol or tocotrienol. The water formed in the esterification reaction can be continuously removed by azeotropic distillation with the aid of the hydrocarbon used as solvent, and can be removed in a water trap. The excess carboxylic acid can, e.g. in the case of sorbic acid, be removed by crystallization after the reaction is complete and the reaction mixture has cooled.
On use of a two-phase mixture consisting of an aliphatic hydrocarbon and a 5-membered cyclic carbonate of the formula II or a xcex3-lactone of the formula III for the esterification according to the invention it is generally necessary to employ the carboxylic acid only in equimolar amounts or else in a slight excess (up to about 100 mol % excess).
On use of mixtures consisting of a suitable hydrocarbon and a 5-membered cyclic carbonate or 5-membered lactone the water formed in the esterification is removed by distillation in a ternary azeotropic mixture. The lower phase in the fitted water trap then contains the water in the form of a solution in the carbonate or the xcex3-lactone and is removed, and the hydrocarbon is allowed to flow back continuously into the reaction vessel. The 5-membered cyclic carbonate or xcex3-lactone which has distilled out must be continuously replaced by new, ie. anhydrous, carbonate or xcex3-lactone in the reaction vessel. A great advantage of this variant of the process is that there is no need to remove large excesses of carboxylic acids, and the resulting tocopheryl ester or tocotrienyl ester can be isolated in very pure form from the hydrocarbon solution which can be easily removed as upper phase. The 5-membered cyclic carbonate or xcex3-lactone in the lower phase can be used for further esterifications after workup.
The process according to the invention is very particularly important for preparing xcex1-tocopheryl sorbate, which is in demand as sunscreen agent or for antiacne treatment, because the esterification of tocopherols with unsaturated carboxylic acids represents a particular problem. The all-E-tocopheryl sorbate which is of particular interest for cosmetic use can also be prepared very advantageously by the process according to the invention without isomerization of the double bonds in the tocotrienol moiety or in the sorbic acid moiety. The process according to the invention is, therefore, to be illustrated hereinafter by the esterification of VE with sorbic acid.
Tocopheryl sorbate can advantageously be prepared by the process according to the invention when
a) 2.5 to 6, preferably 4 to 5, mol of sorbic acid are used per mole of tocopherol for the esterification of VE, and
b) the reaction is carried out at from 110 to 130xc2x0 C. in a hydrocarbon boiling in the range from 80 to 200xc2x0 C.
In the process according to the invention, it is advantageous to prepare essentially all-E-tocopheryl sorbate by
a) using from 4.5 to 5.5 mol of sorbic acid per mole of all-E-tocopherol and
b) carrying out the reaction at from 113xc2x0 C. to 120xc2x0 C. in petroleum spirit boiling in the range from about 80 to 140xc2x0 C.
To isolate tocopheryl sorbate in this variant of the process it is advantageous to cool the reaction mixture after the esterification to from 0 to 5xc2x0 C., and to filter off the excess sorbic acid which crystallizes out before working up the reaction mixture in a conventional way.
Another advantageous variant of the process according to the invention comprises preparing tocopheryl sorbate by
a) using about 1.0 to 2.5 mol of sorbic acid per mole of tocopherol and
b) carrying out the reaction in a mixture of an aliphatic or cycloaliphatic hydrocarbon boiling in the range from 80 to 200xc2x0 C. and propylene carbonate or xcex3-butyrolactone.
The process according to the invention is very particularly advantageous when tocopheryl sorbate is prepared by
a) using about 1.5 mol of sorbic acid per mole of tocopherol and
b) carrying out the reaction in a mixture of octane and 1,2-propylene carbonate at about 110 to 130xc2x0 C.
The procedure for this variant of the process is advantageously such that the tocopherol and the sorbic acid are introduced into the mixture of octane and 1,2-propylene carbonate or xcex3-butyrolactone, concentrated sulphuric acid is added dropwise as catalyst, then the reaction mixture is refluxed for from 3 to about 15 hours, with the water formed in the reaction being removed by azeotropic distillation and being continuously separated out in the form of a solution in propylene carbonate or xcex3-butyrolactone which results as lower phase from the condensate collected in a trap and the propylene carbonate or xcex3-butyrolactone being replaced by anhydrous propylene carbonate or xcex3-butyrolactone, and where finally the required tocopheryl sorbate is isolated from the octane phase in a conventional way.